The proposal describes a 5-year plan wherein the candidate will complete his training to be an independent clinical investigator with a focus on inhibitors of angiogenesis as cancer therapeutics. During the course of his fellowship and first year as faculty in Medical Oncology, Dr. Flaherty has gained experience in the design and conduct of early phase clinical trials with investigational agents under the supervision of the sponsor, Dr. O'Dwyer. The studies that Dr. Flaherty has authored establish his ability to coordinate a multidisciplinary effort to understand the mechanisms of action and resistance for experimental targeted therapies. This award will allow Dr. Flaherty to complete a Master's Degree in Patient Oriented Research. During the course of the proposed project Dr. Flaherty will conduct a series of clinical trials that will further the understanding of the use of inhibitors of angiogenesis in the treatment of solid tumors. By the end of the 5-year period, Dr. Flaherty will be in a position to compete for peer-reviewed funding to extend these findings. There are substantial preclinical data to suggest that combining VEGF signaling inhibitors with agents that target other mediators of angiogenesis results in synergistic inhibition of angiogenesis. The principal hypothesis of the project is that effective inhibition of angiogenesis will require combining agents that target critical signaling mediators in endothelial cells and pericytes. To this end, we propose a series of clinical trials combining investigational agents targeted against signaling pathways involved in angiogenesis. These combinations are based on the pairing of a VEGF inhibitor with inhibitors of the PDGF receptor, EGF receptor, and Raf tyrosine kinases. We propose to characterize tumor microvasculature prior to treatment with the proposed anti-angiogenesis regimens with the purpose of identifying markers that are strongly correlated with therapeutic benefit. We also propose to evaluate dynamic contrast-enhanced MRI and Doppler ultrasound as modalities to identify, at an early point in the treatment course, which patients are likely to attain prolonged clinical benefit. Dr. Flaherty's mentor, Dr. O'Dwyer, is director of the Developmental Therapeutics Program at the University of Pennsylvania Cancer Center. He is a recognized leader in the field of investigational therapies, has a record of mentoring successful clinical researchers, and is committed to Dr. Flaherty's training.